Blood low density lipoproteins(LDL) carry cholesterol into blood vessel walls where the cholesterol can accumulate causing atherosclerotic plaques, the cause of most heart attacks and strokes. LDL is susceptible to aggregate and this promotes LDL retention within the vessel wall. Accumulation of LDL in the vessel wall attracts scavenger cells such as macrophages. Under some conditions macrophages take up LDL, degrade it, and store LDL's cholesterol in lipid droplets. Our research has focused on a novel macrophage endocytic pathway that results in a different fate for LDL cholesterol within macrophages. Incubation of aggregated low density lipoproteins(AgLDL)and other small hydrophobic particles with macrophages leads to their accumulation within a large cytoplasmic labyrinth of surface-connected compartments(SCC)by a process we have named patocytosis. In contrast to rapid and complete degradation of LDL that enters macrophages by coated-pit type endocytosis, most AgLDL that enters macrophages by patocytosis is not degraded. Interestingly, macrophages can reverse LDL aggregation when AgLDL is taken up by patocytosis. Macrophages disaggregate and release AgLDL from SCC when the macrophages are exposed to plasminogen in serum. Macrophages convert inactive serum plasminogen to the active protease, plasmin. This plasmin partially degrades the accumulated AgLDL causing it to disaggregate and release from macrophage SCC. Because aggregation of LDL contributes to its retention in atherosclerotic plaques, macrophage reversal of LDL aggregation should facilitate removal of LDL from atherosclerotic plaques. We have now discovered that activation of macrophages causes AgLDL in SCC to be transferred to and metabolized in lysosomes. This prevents plasmin-mediated release of LDL cholesterol from macrophages, and results in LDL cholesterol storage in macrophage lipid droplets, which could contribute to the buildup of cholesterol in atherosclerotic plaques.